Disruption of the plasminogen activator inhibitor-1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice

Abstract

Elevated levels of plasma and adipose tissue plasminogen activator inhibitor-1 (PAI-1) are observed frequently in obese humans and rodents. In this report, genetically obese (ob/ob) mice lacking the PAI-1 gene (PAI-1(-/-)) were generated and then used to test the hypothesis that the presence of PAI-1 promotes the hyperglycemia, hyperinsulinemia, and insulin resistance associated with obesity. Both wild-type (WT) ob/ob and PAI-1(-/-) ob/ob mice developed substantial adiposity compared with their lean counterparts. However, the PAI-1(-/-) ob/ob mice weighed significantly less than the WT ob/ob mice, and their hyperglycemia and hyperinsulinemia improved significantly. Although intraperitoneal glucose administration resulted in a dramatic increase in serum insulin levels in WT ob/ob mice, the increase in PAI-1(-/-) ob/ob mice was relatively small. Reverse transcription polymerase chain reaction assays and in situ hybridization studies demonstrated that tumor necrosis factor alpha (TNF-alpha) mRNA expression increased significantly in the adipose tissue of WT ob/ob mice at most ages tested. However, it was not increased, or only mildly increased, in the adipose tissue of the PAI-1(-/-) ob/ob mice. The concentration and rate of secretion of TNF-alpha protein in adipose tissue from PAI-1(-/-) ob/ob mice also were significantly lower compared with their WT ob/ob counterparts as shown by immunohistochemistry and ELISA. These results suggest that PAI-1 contributes to the development of the characteristic hyperglycemia and hyperinsulinemia associated with murine obesity, possibly by facilitating increased adipose tissue TNF-alpha gene expression.